Purpose
Prostate-specific membrane antigen (PSMA) expression has been observed in a subset of soft tissue sarcomas, mainly in the neovascular endothelial cells. This feasibility study aimed to evaluate PSMA expression and PSMA PET/CT imaging in metastatic soft tissue sarcoma, providing important insights for potential future exploration of PSMA-targeted radioligand therapy.

Methods
This prospective single-center study included adult patients with metastatic soft tissue sarcoma, with measurable disease (lesion diameter > 1 cm), available biopsy/resection material, ECOG/WHO performance status of 0–2 and either no prior systemic treatment, progressive disease during/after treatment, or stable disease/partial response with the last dose > 8 weeks prior. Immunohistochemical PSMA staining was performed on previously obtained biopsy or resection material. In case of high PSMA expression, a [18F]-JK-PSMA-7 PET/CT scan evaluated tracer uptake, with adequate uptake defined as SUVmax > 8.

Results
Of 25 included patients, 11 (44%) had high PSMA expression: 4/11 leiomyosarcomas, 3/4 dedifferentiated liposarcomas, 2/5 undifferentiated pleomorphic sarcomas, 1/2 myxofibrosarcomas and 1/1 malignant peripheral nerve sheath tumour. Five of 11 patients agreed to a [18F]-JK-PSMA-7 PET/CT, of which 3 had lesions that showed adequate tracer uptake (SUVmax 10.7–16.7). However, uptake across all metastatic lesions was highly heterogeneous (median SUVmax = 3.8; range 0.5–16.7), indicating that these patients are unlikely to benefit sufficiently from PSMA-targeted therapy. The study was therefore terminated prematurely.

Conclusion
PSMA expression and PSMA tracer uptake in metastatic soft tissue sarcoma were highly heterogeneous. A deeper understanding of PSMA biology and improved patient selection criteria are essential for future application of PSMA-targeted radioligand therapy in this disease.

BACKGROUND: In patients with nonischemic cardiomyopathy and no late gadolinium enhancement (LGE) on cardiac magnetic resonance, risk prediction for the occurrence of sustained ventricular arrhythmias (VA) is challenging. Global and regional sympathetic denervation has been associated with VA in patients with ischemic cardiomyopathy. Its prognostic relevance in nonischemic cardiomyopathy is unknown. METHODS: Consecutive patients from the Leiden Nonischemic Cardiomyopathy Study who underwent programmed electrical stimulation, LGE-cardiac magnetic resonance, and 123-iodine meta-iodobenzylguanidine imaging between 2011 and 2019 were included. The presence of LGE and global and regional sympathetic denervation on 123-iodine meta-iodobenzylguanidine were evaluated, and patients were followed for the occurrence of VA. Global denervation was assessed using the heart-to-mediastinum ratio. Regional denervation was evaluated by calculating the number of denervated segments (DS), the ratio of DS, the summed defect score, and the weighted denervation size. RESULTS: Of 75 included patients (median age 63 years [25th-75th interquartile range (IQR) 54-68], 79% male, left ventricular ejection fraction 36% [IQR, 27-44], 37% inducible for VA), 35 had no LGE. During 4.5±1.6 years of mean follow-up, VA occurred in 8 of 35 (23%) patients without LGE and in 18 of 40 (45%) patients with LGE. Among patients without LGE, those with VA had greater regional sympathetic denervation (median number of DS 8 [IQR, 7-10] versus 2 [IQR, 1-5], P=0.004; median ratio of DS 0.5 [IQR, 0.5-0.7] versus 0.2 [IQR, 0.1-0.4], P=0.007; median defect score 36 [IQR, 30-41] versus 18 [IQR, 14-24], P=0.01; median weighted denervation size 47 [IQR, 38-54] versus 22 [IQR, 14-30]; P=0.01). In bivariate analysis, the number of DS (hazard ratio, 1.25 [95% CI, 1.06-1.46]; P=0.006) was associated with the occurrence of VA in patients without LGE. Denervation of ≥7 segments identified patients without LGE at risk for VA (area under the curve, 0.83; sensitivity, 88%; specificity, 89%). Among patients with LGE, the innervation state was not associated with VA during follow-up. CONCLUSIONS: In patients with nonischemic cardiomyopathy without LGE the extent of regional denervation may contribute to risk stratification for VA.

Background: Prior studies show that short-term treatment using tyrosine kinase inhibitors (TKIs) can reinduce radioiodine uptake and warrant ¹³¹I therapy in radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). We aim to evaluate the potential of standard-of-care TKI lenvatinib to reinduce clinically meaningful radioiodine retention. Methods: Nine RAI-R DTC patients starting lenvatinib treatment for progressive advanced or metastatic disease, were included and underwent rhTSH-stimulated ¹²⁴I dosimetric procedures at baseline, week 6 (N=7) and week 12 (N=8). At all timepoints, the fraction of patients eligible for ¹³¹I therapy with a maximal activity of 7.4 GBq was assessed. Patients were considered eligible if at least one target lesion showed an expected mean absorbed dose ≥20 Gy. In total, 23 target lesions were segmented on¹²⁴I PET/CT images and their volumes estimated using low-dose CT images. Lesion size-specific recovery correction was applied to the measured mean activity concentration at each timepoint. Tumor dosimetry was performed using a mono-exponential fit and S-values from an internal dosimetry program for diagnostic nuclear medicine based on the ICRP adult reference voxel phantoms (IDAC-Dose2.1). Mean absorbed lesion dose per administered activity (LDpA), 24h-uptake and residence time in target lesions were compared between time points. Results: By our definition, none of the patients were found eligible for ¹³¹I therapy at any timepoint. Lenvatinib-induced partial response was observed in 59% and 75% of target lesions at week 6 and 12, respectively. Median LDpA was 0.08 (IQR: 0.04-0.17), 0.18 (0.08-0.36) and 0.17 (0.09-0.37) Gy/GBq for week 0, 6 and 12, respectively (p=0.08). The 24h-uptake and residence time were comparable between timepoints (p>0.22). Conclusion: Redifferentiation of RAI-R DTC to reinduce radioiodine uptake to a level that warrants ¹³¹I therapy may not be established by short-term lenvatinib treatment. Multi-targeted TKIs may not be as potent as selective TKIs in reinducing clinically meaningful radioiodine retention.

Background and aims
Immune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.

Methods
Patients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.

Results
We included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p < 0.001) and in patients without calcifications (p = 0.013).

Conclusions
A significant increase in arterial inflammation as measured on [18F]FDG PET/CT was observed in patients with advanced melanoma treated with ICIs only in the first six months after initiation of therapy, whereas no changes were observed in the control group. Moreover, arterial inflammation was mainly increased in patients without pre-existing inflammatory activity and with non-calcified lesions.

OBJECTIVE: In this pilot study, we investigated the feasibility of response prediction using digital [ 18 F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial. METHODS: Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [ 18 F]FDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P  ≤ 0.2, promising predictive features for response were selected. RESULTS: Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features. CONCLUSION: Both multiparametric MRI and [ 18 F]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT.

Purpose: Navigational strategies create a scenario whereby percutaneous needle-based interventions of the liver can be guided using both pre-interventional 3D imaging datasets and dynamic interventional ultrasound (US). To score how such technologies impact the needle placement process, we performed kinematic analysis on different user groups. Methods: Using a custom biopsy phantom, three consecutive exercises were performed by both novices and experts (n = 26). The exercise came in three options: (1) US-guidance, (2) US-guidance with pre-interventional image-registration (US + Reg) and (3) US-guidance with pre-interventional image-registration and needle-navigation (US + Reg + Nav). The traveled paths of the needle were digitized in 3D. Using custom software algorithms, kinematic metrics were extracted and related to dexterity, decision making indices to obtain overall performance scores (PS). Results: Kinematic analysis helped quantifying the visual assessment of the needle trajectories. Compared to US-guidance, novices yielded most improvements using Reg (PS_avg(US) = 0.43 vs. PS_avg(US+Reg) = 0.57 vs. PS_{avg(US+Reg+Nav)} = 0.51). Interestingly, the expert group yielded a reversed trend (PS_avg(US) = 0.71 vs PS_avg(US+Reg) = 0.58 vs PS_{avg(US+Reg+Nav)} = 0.59). Conclusion: Digitizing the movement trajectory allowed us to objectively assess the impact of needle-navigation strategies on percutaneous procedures. In particular, our findings suggest that these advanced technologies have a positive impact on the kinematics derived performance of novices.

Scope: Abdominal obesity is one of the main modifiable risk factors of age-related cardiometabolic disease. Cardiometabolic disease risk and its associated high abdominal fat mass, cholesterol, and glucose concentrations can be reduced by a healthier lifestyle. Hence, the aim is to understand the relation between lifestyle-induced changes in body composition, and specifically abdominal fat, and accompanying changes in circulating metabolic biomarkers. Methods and results: Data from the Growing Old Together (GOTO) study was used, which is a single arm lifestyle intervention in which 164 older adults (mean age 63 years, BMI 23–35 kg/m²) changed their lifestyle during 13 weeks by 12.5% caloric restriction plus 12.5% increase in energy expenditure. It is shown here that levels of circulating metabolic biomarkers, even after adjustment for body mass index, specifically associate with abdominal fat mass. The applied lifestyle intervention mainly reduces abdominal fat mass (−2.6%, SD = 3.0) and this reduction, when adjusted for general weight loss, is highly associated with decreased circulating glycerol concentrations and increased HDL diameter. Conclusion: The lifestyle-induced reduction of abdominal fat mass is particularly associated, independent of body mass index or general weight loss, with decreased circulating glycerol concentrations and increased HDL diameter.